GLUCOCORTICOID RECEPTOR--STRUCTURE AND FUNCTION

候选人Mark Danielsen博士是最近任命的助理 系里的教授。 R 01的第一年是富有成效的 他开始与其他研究小组合作 在这所大学内外都是如此 该部门将非常 强调研究，并认识到年轻的教师需要 如果他们要发展一个有声望的， 资金充足的研究项目 教学/委员会的负担很轻， 第一年或第二年，然后稳步增长。 如果RCDA被授予 部门承诺不应超过他的时间的10%。 目前50% 他的时间被占用与非研究活动，这将 毫无疑问，在没有RCDA的情况下增加。 如果RCDA被授予 国防部将进一步支持候选人， 包括人员和物资 这应该能让丹尼尔森博士 一些新的项目和合作，不是由他资助的， 当前R 01。 这项建议的重点是激素结合域的糖皮质激素 受体（GR），旨在阐明以下问题： 1)激素结合位点的结构决定因素是什么？（二） 激素结合如何激活受体？ 这个问题将从两个方面来处理。 首先，混合受体将 主要是GR，但其中有小区域的， 孕酮或雄激素受体激素结合结构域替代GR 顺序 这些受体将被分析其结合到 GR激动剂和拮抗剂（包括孕酮）和雄激素。 当结合发生时，激素激活受体的能力将降低。 被研究。 第二种方法是在组织培养中选择细胞 含有突变受体的，a）变得不依赖激素，或 B）需要降低激素水平，或c）可被有效激活 通过通常是部分激动剂和/或拮抗剂的化合物。 这些 通过克隆和测序来表征受体。作为长期 设计GR的激素结合结构域和选择的杂交体/突变体 将在过表达系统中表达以产生足够的 蛋白质结构研究。

The candidate, Dr. Mark Danielsen, is a recently appointed Assistant Professor in this Department. The first year of his R01 was productive and he has begun to develop collaborations with other research groups both within and outside this University. The Department places a very strong emphasis on research and recognizes that younger faculty require support during their formative years if they are to develop a prestigious and well funded research program. Teaching/committee loads are light in the first year or two and then steadily increase. If an RCDA is awarded Department commitments should not exceed 10% of his time. At present 50% of his time is taken up with non-research activities, and this would undoubtedly increase in the absence of an RCDA. If an RCDA is awarded the Department will further support the candidate by providing funds for both personnel and supplies. This should enable Dr. Danielsen to develop a number of new projects and collaborations that are not funded by his current R01. This proposal focuses on the hormone binding domain of the glucocorticoid receptor (GR) and is designed to shed light on the following questions: 1) What are the structural determinants of the hormone binding site? 2) How does hormone binding activate the receptor? The problem will be approached in two ways. First, hybrid receptors will be made which are mainly GR but which have small regions of either the progesterone or androgen receptor hormone binding domain replacing the GR sequence. These receptors will be analyzed for their ability to bind to GR agonists and antagonists (including progesterone) and to androgens. When binding occurs, the ability of the hormone to activate receptor will be studied. The second approach is to select for cells in tissue culture that contain mutant receptors that have a) become hormone independent, or b) require reduced levels of hormone, or c) can be activated efficiently by compounds that are usually partial agonists and/or antagonists. These receptors will be characterized by cloning and sequencing. As a long term project the hormone binding domain of the GR and selected hybrids/mutants will be expressed in an overexpression system to produce sufficient protein for structural studies.